HIV Infection and AIDS

HIV Infection and AIDS


David Kramer, M.D.



I. HIV Transmission Categories

A. Risk Factors in Adults

1. Male sex with male (MSM) 42-45%

2. Injection drug use (IDU) 26-31%

3. Heterosexual 11%

4. Transfusion 1%

a. Less than one in 700,000 units of blood is HIV infected because it is missed by routine screening

5. Hemophilia 1%

6. Undetermined 15%

B. Risk factors in children (<13 years of age)

1. Perinatal 91%

2. Risk unidentified 5%

a. Majority of pediatric cases are caused by perinatal

transmission

3. Transfusion 3%

4. Hemophilia 1%

II. Epidemiology

A. Epidemiology of HIV Infection in Adolescents (13-19 years of age)

1. 15% of adult AIDS cases were acquired during adolescence

2. 25% of heterosexually acquired AIDS cases were infected as teens

3. Serious immune dysfunction at presentation is common

a. Adolescents have a shorter survival time after HIV diagnosis than adults

b. Severity of immune dysfunction suggests long-standing or advanced disease is usually present at

diagnosis

4. Risk factors in adolescents vary by gender

a. Higher proportion of females are infected in the adolescent age group than in any other age group

b. Cause of Infection in Female Teens

(1) Heterosexual contact (54-76%)

(2) Intravenous drug use (16%)

c. Cause of Infection in Male Teens

(1) Received contaminated blood products (46%)

(2) Male sexual contact (33%)

B. Epidemiology of HIV Infection in Women

1. Increasing numbers and percentage of women

2. 20% of 1995 cases were women

3. Third leading cause of death in women of child-bearing age

C. Epidemiology of HIV Infection in Children (<13 years of age)

1. The number of perinatally acquired AIDS cases reported to the CDC declined 27% between 1992 and

1995

2. The cause of the decline was probably more effective antiretroviral therapies and in part because of effect

of perinatal ZDV therapy

3. More than 7,000 children have AIDS

4. >21,000 children have HIV infection

D. Racial and ethnic minority populations

1. AIDS is disproportionately represented among women, children and adolescents with AIDS

2. Reported cases per 100,000 children

a. African-American non-Hispanic - 6.4

b. Hispanic - 2.3

c. White non-Hispanic - 0.4

III. Perinatal Transmission



A. Risk factors in mothers giving birth to HIV-infected children

1. Increasing proportion were infected through heterosexual transmission;

approximately 40%

2. 40% of women have unidentified risk. They probably were infected heterosexually by men unrecognized

to be HIV-infected

3. Transmission because of intravenous drug use decreased to 20%

4. Transfusion-associated infection is extremely rare

B. Timing of Transmission Perinatally Acquired HIV Infection

1. In Utero transmission accounts for 30-50% of perinatally acquired disease. Associated with more rapidly

progressive disease.

2. Intrapartum transmission accounts for 50-70% of perinatally acquired disease. This period affords the

best opportunity for interruption of transmission.

C. Postpartum transmission (breast feeding)

1. The risk of transmission is14%

2. The risk of transmission from a mother who seroconverts while breast feeding is 29%

3. Women with HIV or at risk for HIV living in developed countries should not breast feed

D. Interruption of Vertical Transmission. Administration of AZT therapy during pregnancy, labor and delivery,

and to the infant for the first 6 weeks of life reduces the transmission rate from 25% to 8%.

IV. Immunopathogenesis

A. Constant high-level replication of the virus

1. Approximately one billion viral particles per day are replicated

B. High steady-state level of virus in the blood

C. Immune clearance of virus

1. Production of CD4 cells initially matches viral replication

2. Progressive depletion of CD4 cells occurs

3. Eventual profound immunologic dysfunction intercedes

V. Characteristic Immunologic Disturbances in AIDS

A. Laboratory T-cell abnormalities

1. Decreased number and function of CD4+ T cells

2. Impaired CD8 T-cell cytotoxicity

3. Impaired mitogen and antigen responses

4. Impaired cytokine production (IL-2, (IFN, etc)

B. Clinical T-cell abnormalities

1. Impaired delayed-type hypersensitivity

2. Chronic active viral infections (VZV, CMV, EBV)

3. Opportunistic infections

C. Laboratory B-cell abnormalities

1. Hypergammaglobulinemia

2. Impaired specific antibody responses

a. Primary and secondary

b. T-cell-dependent and independent antigens

D. Clinical B-cell Abnormalities

1. Recurrent bacterial infections

a. Encapsulated organisms most common

(1) S. pneumoniae

(2) H. influenzae

VI. Measurements of Viral Load (VL)

A. Assays Currently Available

1. RNA polymerase chain reaction (RNA-PCR)

2. Branched chain DNA (bDNA)

3. Nucleic acid amplification assay (NASBA)



B. In adults, viral load is predictive of disease progression, independent of CD4 count

1. >100,000 copies/ml--rapid deterioration

2. <10,000 copies/ml--stable course

C. Predictors of Perinatal Transmission. Higher maternal viral loads are associated with increased

transmission. However, even women with undetectable viral loads can transmit infection

D. In children with perinatally-acquired disease, viral loads are much higher than adults (by 1-2 logs)

1. Peak at 1-2 months of age (up to 1,000,000 copies/ml)

2. Slow decline over time (50,000 - >200,000 by age 2 years)

3. Lower viral loads are present in slow progressors as compared to rapid progressors

VII. CDC Classification System for HIV Infection in Children

A. Classifies children on basis of symptoms/disease manifestations and level of immune suppression

1. Clinical categories

a. Category N: not symptomatic

b. Category A: mildly symptomatic

c. Category B: moderately symptomatic

(1) The only AIDS-defining illness in this category is lymphocytic interstitial pneumonitis (LIP)

d. Category C: severely symptomatic

(1) All other AIDS-defining illnesses

2. Immunologic categories (based on CD4 counts and percentage)

a. Category 1: no evidence of suppression

b. Category 2: moderate suppression

c. Category 3: severe suppression

B. Classification provides a comprehensive assessment of child's overall status

C. Classification is used to define progressive disease or clinical endpoints in research trials

VIII. Clinical Presentation of HIV Infection by Symptom Complex

A. Common nonspecific findings (most in CDC category A)

1. In General, most common presenting findings

2. Oral thrush

3. Lymphadenopathy

4. Hepatosplenomegaly

5. Recurrent diarrhea

6. Poor growth

B. Neurologic manifestations (CDC category C)

1. Developmental delay/loss of milestones

2. Progressive symmetrical motor deficits

3. Cerebral atrophy. Infection may present as acquired microcephaly

4. Basal ganglia calcifications

5. Chronic encephalopathy or dementia

C. Lymphocytic interstitial pneumonitis (LIP) (CDC category B)

1. Most common chronic pulmonary process

2. Often associated with parotitis and digital clubbing

3. Insidious development of hypoxemia is common, which is usually reversible with corticosteroids

4. Probably associated with EBV infection

D. Infectious complications

1. Chronic otitis media and sinusitis (CDC category A)

a. Typical pathogens most common

b. S. aureus, coagulase negative staph, and P. aeruginosa are detected in chronic draining ears

2. Recurrent and chronic herpesvirus infections (HSV, VZV). May require prophylaxis or chronic acyclovir

therapy

3. Recurrent serious bacterial infections (CDC category C)

a. Pneumonia. Multiple episodes may lead to bronchiectasis



b. Bacteremia

4. Opportunistic infections (CDC category C)

a. Occur when CD4 count extremely low

b. Pneumocystis carinii pneumonia

c. Cryptosporidiosis

d. Disseminated CMV

e. Disseminated Mycobacterium Avium Complex (MAC)

f. Disseminated fungal infections (Candida sp., Aspergillus sp., rarely Cryptococcus sp.)

E. Neoplasms

1. B-cell lymphoma, CNS lymphoma

2. Kaposi's sarcoma (exceedingly rare)

3. Smooth muscle tumors

F. Other conditions associated with HIV

1. Wasting syndrome

2. Cardiomyopathy

3. Nephropathy

4. Hematologic abnormalities

a. Anemia, thrombocytopenia, neutropenia

b. Absolute lymphopenia

5. Dermatologic diseases

a. Disseminated molluscum contagiosum and flat warts

b. Seborrheic dermatitis

IX. Bimodal Presentation of Pediatric Disease

A. Rapid progressors account for 30% of HIV-infected Patients

1. Onset of symptoms occur in first months of life

a. Failure to thrive

b. Opportunistic infections

c. Encephalopathy

2. Death generally occurs within 3 years

3. High peak viral loads and low CD4 counts

B. Slow progressors account for 70% of HIV-infected Patients

1. These patients are asymptomatic and without physical findings up to several years

2. Life expectancy is >5 years

3. Most common symptom complexes include generalized lymphadenopathy, lymphocytic interstitial

pneumonia, and recurrent bacterial infections

4. Subtle presentations or maternal risk factors may be the only findings in asymptomatic cases

5. Children infected via transfusion or sexual transmission are more likely to have slowly progressive

disease

X. Diagnosis

A. Assays for early diagnosis of perinatally-acquired disease

1. RNA PCR

a. Using NASBA assay, 56% of 36 infected infants had positive test by 14 days of age vs. 33% using

DNA PCR

2. HIV antibody is not definitive because of passive maternal transfer across the placenta

B. Early Diagnostic Evaluation for Perinatally-acquired Disease

1. Perform PCR or culture at birth, 1 month and 3-4 months

a. HIV diagnosis requires 2 positive results that must be at different time points

(1) Definitive diagnosis is usually possible within first 1-3 months of life

(a) Diagnosis is excluded if more than 2 negative results have been obtained, both performed

greater than1 month of age

(b) One performed >4 months of age



2. ICD p24 antigen test

a. If positive, the test may be used to confirm a positive PCR or HIV culture

b. If negative, must repeat PCR or culture

C. Diagnosis of children >18 months of age

1. HIV antibody by western blot

2. Positive results on >two different blood samples

XI. Antiretroviral Therapy

A. Nucleoside Reverse Transcriptase Inhibitors

1. Zidovudine (AZT, ZDV)

a. 120-180 mg/m2/dose po q6-8 hrs

b. Adverse Effects. Anemia and granulocytopenia are the major toxicities. Elevated transaminases are

less common

c. Monotherapy results in 0.5 log decrease in viral load

d. CSF:plasma ratio 60%

2. ddI (didanosine)

a. 90 mg/m2/dose po q12 hrs

b. Major toxicities include pancreatitis and peripheral neuropathy.

c. Monotherapy results in 0.6 log decrease in viral load

3. ddC (zalcitabine)

a. 0.01 mg/kg/dose po TID. Pharmacokinetics suggest this dose may be too low

b. Same toxicities as ddI

4. d4T (stavudine)

a. 1 mg/kg/dose q12 hr

b. Peripheral neuropathy is the major (but rare) toxicity

c. Penetrates CNS

5. 3TC (lamivudine)

a. 4 mg/kg/dose q12 hr

b. Peripheral neuropathy is the primary toxicity (rare)

c. Concurrent use with AZT will suppress HIV resistance to AZT

d. If used as monotherapy, resistance develops rapidly.

B. Non-nucleoside Reverse Transcriptase Inhibitors

1. Nevirapine

a. 120 mg/m2/dose BID

b. Causes 1 log drop in viral load rapidly

c. Penetrates CNS

d. Resistance develops rapidly (especially as monotherapy)

e. Rash is the major (but uncommon) toxicity; may progress to Stevens-Johnson syndrome

2. Delavirdine

a. Similar efficacy as nevirapine

b. Drug-drug interactions with protease inhibitors

c. No published pediatric data

C. Protease Inhibitors (PI's)

1. Overview

a. Interrupts viral assembly and infectivity

b. When combined with nucleosides, they produces a precipitous drop in viral load (1-2 logs) in adults

c. Significant drug-drug interactions

d. Entering clinical trials in children

2. Indinavir (Crixivan)

a. Pediatric formulation is not available (only capsules)

b. The major toxicity is nephrolithiasis (2-5%)



3. Ritonavir (Norvir)

a. First PI available in suspension formulation

b. Side effects

(1) Unpalatable and GI intolerance

(2) Circumoral paraesthesias

(3) Complete inhibition of p450 metabolic pathway leads to a significant increase in levels of drugs

metabolized via this route (rifabutin)

4. Nelfinavir mesylate (Viracept)

a. Available as a powder for suspension

b. Diarrhea (rarely)

5. Saquinavir (Invirase)

a. Pediatric formulation is not yet available

b. Poor bioavailability limits serum drug levels. Last potent of all PI's

c. When used in combination with ritonavir, the levels of saquinavir increase substantially

D. Antiretroviral drug resistance

1. Rapid development of resistance occurs with monotherapy

a. 89% of persons with late-stage disease have ZDV resistance after one year of monotherapy vs 31%

with less advanced disease

2. High viral turnover promotes selection of drug-resistant mutants. Mutants have specific amino acid

substitutions in reverse transcriptase or protease enzyme. Complete suppression of replication decreases

selection of mutants.

E. Goals of Combination Antiretroviral Therapy

1. Complementary drug interactions. Drugs act at different points in replication cycle

2. Reduction or delay in development of drug-resistant mutants

a. Significantly decreasing viral load, fewer drug resistant mutants

b. With multiple drugs, more mutations are necessary to develop resistance

3. Monotherapy is no longer recommended (except for prevention of vertical transmission)

F. General Principles of Combination Therapy

1. Check for drug-drug interactions

2. Monitor laboratory values based on expected drug toxicities

3. Some examples of combination regimens in use

a. 2 nucleosides (eg. ZDV + ddI, ddC or 3TC, d4T + 3TC)

(1) ZDV and d4T are antagonistic in combination

b. 1 nucleoside plus 1 non-nucleoside (eg. ZDV + nevirapine)

c. 2 nucleosides + a protease inhibitor (eg. ZDV + 3TC + ritonavir)

d. 1 nucleoside + a non-nucleoside + a protease inhibitor (eg. ZDV + nevirapine + ritonavir)

G. Initiation of Antiretroviral Therapy

1. Consideration should be given to treating all infants/children at diagnosis

2. Current Recommendations for Antiretroviral Therapy:

a. Significant symptoms

b. Falling CD4 count

c. No consensus on viral load "threshold" of 100,000 copies/ml

d. Some favor highly aggressive therapy (3 drug) to prevent progressive disease ("hit early, hit hard")

XII. Outpatient Management of the HIV-infected child

A. Monitor immunologic function and viral load regularly (Q3-6 Months)

B. Nutritional Assessment every 3 Months

C. Developmental and neuropsychological assessment q3-6 months

1. Physical/occupational therapy

2. Speech therapy

3. Play therapy



D. Provide immunizations with following exceptions:

1. Substitute inactivated enhanced polio vaccine (IPV) for live attenuated polio vaccine

2. Withhold MMR in CDC immunologic category 3

3. Add pneumococcal vaccine

4. Influenza vaccine yearly

5. Varicella vaccine under investigation in this population

E. Prophylaxis against opportunistic infections

XIII. Infection Control in Household Setting, Day Care or School

A. Use "universal precautions" for handling all body fluids containing visible blood

B. Immunize family members of HBsAg positive individuals

C. Siblings of HIV-infected children should receive inactivated polio vaccine and varicella vaccine

Cancer Chemotherapy

Cytotoxic drugs, hormones, antihormones, and biologic agents have become increasingly effective means of treating cancer. Many patients are treated on protocols to provide optimal therapy for refractory or poorly responsive malignancies. Treatment may be inadequate or ineffective because of drug resistance of the tumor cells. This has been attributed to spontaneous genetic mutations in subpopulations of cancer cells prior to exposure to chemotherapy. After chemotherapy has eliminated the sensitive cells, the resistant subpopulation grows to become the predominant cell type (Goldie-Coldman hypothesis). This has been the basis of alternating non-cross-resistant chemotherapy regimens. Molecular mechanisms of drug resistance are now the subject of intense study. In many instances, specific drug resistance results from an amplification in the number of gene copies for an enzyme inhibited by a specific chemotherapeutic agent. A more general form of "multidrug resistance" (MDR) has been described in association with expression of a gene (MDR1) encoding a transmembrane glycoprotein of MW 170 (P-glycoprotein) on tumor cells. This protein is an energy-dependent transport pump that facilitates drug efflux from tumor cells and promotes resistance to a broad spectrum of unrelated cancer drugs. Acquired multidrug resistance in multiple myeloma and lymphoma has been reversed clinically by adding the calcium channel blocker verapamil to chemotherapy regimens. Unfortunately, the doses of verapamil required to overcome drug resistance are associated with cardiovascular side effects. High doses of cyclosporine appear to increase the cytotoxicity of etoposide both in vitro and in vivo, probably by inhibiting the function of P-glycoprotein. The use of cyclosporine to enhance the effect of etoposide in purging resistant tumor cells in vitro from autologous bone marrow is under investigation. Cyclosporine has also been shown to enhance the cytotoxic effect of multiagent chemotherapy against resistant multiple myeloma. Verapamil and cyclosporine increase the accumulation and cytotoxicity of daunorubicin in myeloid leukemia cells, enhancing cell kill. MDR modulators will need to be both less toxic and more potent to be clinically useful. An example is the cyclosporine analog PSC 833, with little of the immunosuppressive effects or renal toxicities of cyclosporine but with five- to tenfold greater MDR-modulating activity. Chemotherapy is used to cure a small percentage of malignancies, as adjuvant therapy to decrease the rate of relapse or improve the disease-free interval, and to palliate symptoms in some patients with incurable malignancies. In addition, chemotherapy may play a role as preoperative or "neoadjuvant" therapy to reduce the size and extent of the primary tumor, thereby allowing complete excision at the time of surgery. Chemotherapy was first shown to be curative in the treatment of advanced stages of choriocarcinoma in women. It is also curative in Hodgkin's disease, diffuse large-cell and some high-grade lymphomas (including Burkitt's), carcinoma of the testis, some cases of acute leukemia, and embryonal rhabdomyosarcoma. When combined with initial surgery—and in some instances with irradiation—chemotherapy increases the cure rate in Wilms' tumor and increases the rate of long-term control and cure of breast cancer, colon cancer, rectal cancer, and osteogenic sarcomas. Combination chemotherapy provides palliation and prolongation of survival in adults with Hodgkin's disease, non-Hodgkin's lymphoma, mycosis fungoides, multiple myeloma and macroglobulinemia, acute and chronic leukemias, and breast, ovary, and small-cell lung carcinoma as well as carcinoid. Patients with incurable tumors who desire aggressive treatment should be referred for experimental protocol therapy. Tumor cell vaccines combined with immune adjuncts are under investigation as specific immunotherapy for chemotherapy-resistant tumors such as malignant melanoma. High-dose chemotherapy followed by bone marrow transplantation is curative therapy for various types of leukemia, multiple myeloma, and high-risk lymphoma and testicular cancer. Allogeneic or autologous bone marrow or peripheral blood stem cells with or without ex vivo purging is used depending on the disease. The use of growth factors and blood stem cells has decreased the toxicity and cost of bone marrow transplantation. Autologous transplantation may now be used with low morbidity and mortality on selected patients up to age 70. In addition, dose-intense chemotherapy regimens with autologous bone marrow or peripheral blood progenitor cell rescue are currently being investigated in the high-risk adjuvant or early relapse setting for patients with carcinoma of the breast and ovaries. A small study suggests that intensive doses of chemotherapy followed by bone marrow or peripheral blood stem cell infusion in incurable diseases such as metastatic breast cancer may prolong survival. It is possible that this aggressive approach may be useful even when "cure" is not the objective. While most anticancer drugs are used systemically, there are selected indications for local or regional administration. Regional administration involves direct infusion of active chemotherapeutic agents into the tumor site (eg, intravesical therapy, intraperitoneal therapy, hepatic artery infusion with or without embolization of the main blood supply of the tumor). These treatments can result in palliation and prolonged survival. A summary of the types of cancer responsive to chemotherapy and the current treatments of choice is offered in Table 4–3. In some instances (eg, Hodgkin's disease), optimal therapy may require a combination of therapeutic resources, eg, radiation plus chemotherapy rather than either modality alone. Patients with stages I, II, and IIIA Hodgkin's disease are often treated with radiation alone, avoiding the potential toxicity of systemic chemotherapy. A small percentage of these patients may require chemotherapy later for disease recurrence.
Table 4–3. Treatment choices for cancers responsive to systemic agents.
Diagnosis
Acute lymphocytic leukemia
Acute myelocytic and myelomonocytic leukemia
Chronic myelocytic leukemia
Chronic lymphocytic leukemia
Hairy cell leukemia Hodgkin’s disease (stages III and IV)
Non-Hodgkin’s lymphoma
Multiple myeloma
Waldenström’s macroglobulinemia
Polycythemia vera
Carcinoma of lung Small cell Non-small cell3
Carcinoma of the head and neck3 Carcinoma of the esophagus3 Carcinoma of the stomach and pancreas3
Carcinoma of the colon and rectum3
Carcinoma of the kidney3
Carcinoma of the bladder3
Carcinoma of the testis3
Carcinoma of the prostate3
Carcinoma of the uterus3 Carcinoma of the ovary3
Carcinoma of the cervix3
Carcinoma of the breast3
Current Treatment of Choice
Induction: Combination chemotherapy. Adults:
Vincristine, prednisone, daunorubicin, and asparaginase.
Children: Vincristine, prednisone with or without
asparaginase.
Consolidation: Multiagent alternating chemotherapy.
Allogeneic bone marrow transplant for young adults or
high-risk disease or second remission. CNS prophylaxis
with intrathecal methotrexate with or without whole brain
radiation.
Remission maintenance: Methotrexate, thioguanine.
Induction: Combination chemotherapy with cytarabine
and an anthracycline (daunorubicin, idarubicin).
Tretinoin for acute promyelocytic leukemia.
Consolidation: High-dose cytarabine. Autologous
(with or without purging) or allogeneic bone marrow
transplantation for high-risk disease or second remission.
Hydroxyurea, alpha interferon. Allogeneic bone marrow
transplantation for young patients.

Chlorambucil and prednisone or fludarabine (if treatment
is indicated).

Cladribine (2-chlorodeoxyadenosine; CdA).
Combination chemotherapy: doxorubicin (Adriamycin),
bleomycin, vinblastine, dacarbazine (ABVD) or
mechlorethamine, vincristine, prednisone, procarbazine
(MOPP) or alternating MOPP/ABVD or MOPP/ABV,
autologous bone marrow transplant for high-risk patients
or relapsed disease.
Combination therapy depending on histologic classification
but usually including cyclophosphamide, vincristine,
doxorubicin, and prednisone (CHOP) with or without
other agents. Autologous bone marrow transplantation in
high-risk first remission or first relapse.
Combination chemotherapy: melphalan and prednisone
or melphalan, cyclophosphamide, carmustine,
vincristine, doxorubicin, and prednisone. Autologous
bone marrow transplantation in first complete or partial
remission. Allogeneic bone marrow transplantation for
young patients with poor prognosis disease.
Chlorambucil versus combination chemotherapy:
cyclophosphamide, vincristine, prednisone. Allogeneic
bone marrow transplantation for high-risk young patients.
Hydroxyurea, phlebotomy

Combination chemotherapy: cisplatin and etoposide.
Palliative radiation therapy.
Advanced disease: cisplatin, vinorelbine
Localized disease: cisplatin, vinblastine
Combination chemotherapy: cisplatin and fluorouracil

Combination chemotherapy: fluorouracil, cisplatin,
mitomycin
Stomach: etoposide, leucovorin,2 fluorouracil (ELF)
Pancreas: fluorouracil or ELF, gemcitabine

Colon: fluorouracil plus levamisole (adjuvant) or with
leucovorin.2
Rectum: fluorouracil with radiation therapy (adjuvant)
Floxuridine, vinblastine, IL-2, alpha interferon

Intravesical BCG or thiotepa. Combination
chemotherapy: methotrexate, vinblastine, doxorubicin
(Adriamycin), cisplatin (M-VAC) or CMV alone
Combination chemotherapy: etoposide and cisplatin
Autologous bone marrow transplantation for high-risk or
relapsed disease.
Estrogens or LHRH analog (leuprolide) plus an
antiandrogen (flutamide)

Progestins or tamoxifen
Combination chemotherapy: cyclophosphamide and
cisplatin (or carboplatin) or paclitaxel and cisplatin/
carboplatin
Combination chemotherapy: methotrexate,
doxorubicin, cisplatin, and vinblastine; or mitomycin,
bleomycin, vincristine, and cisplatin
Combination chemotherapy: cyclophosphamide,
doxorubicin, fluorouracil, or cyclophosphamide,
methotrexate, fluorouracil. Tamoxifen for estrogen/
progesterone receptor-positive tumors. Adjuvant therapy
for high-risk patients and for limited metastatic disease:


Other Valuable Agents and Procedures
Doxorubicin, cytarabine, cyclophosphamide, etoposide, teniposide (VM-26),1 allopurinol,2 autologous bone marrow transplantation
Mitoxantrone, idarubicin, etoposide,
mercaptopurine, thioguanine,
azacitidine,1 amsacrine,1
methotrexate, doxorubicin, tretinoin,
allopurinol,2 leukapheresis, prednisone

Busulfan, mercaptopurine,
thioguanine, cytarabine, plicamycin, melphalan,
autologous bone marrow transplantation, allopurinol2
Vincristine, cyclophosphamide, doxorubicin,
Cladribine (2-chlorodeoxyadenosine; CdA),
androgens,2 allopurinol2
Pentostatin (deoxycoformycin), alpha interferon
Carmustine, lomustine, etoposide,
thiotepa, autologous bone marrow transplantation

Bleomycin, methotrexate, etoposide,
chlorambucil, fludarabine, lomustine, carmustine,
cytarabine, thiotepa, amsacrine, mitoxantrone,
autologous or allogeneic bone marrow transplantation

Etoposide, cytarabine, alpha interferon,
dexamethasone, autologous bone marrow
transplantation

Etoposide, alpha interferon, doxorubicin,
dexamethasone, plasmapheresis, autologous bone
marrow transplantation
Busulfan, chlorambucil, cyclophosphamide, alpha
interferon, radiophosphorus 32P
Cyclophosphamide, doxorubicin, vincristine

Doxorubicin, etoposide, mitomycin

Methotrexate, bleomycin,
hydroxyurea, doxorubicin, vinblastine
Methotrexate, bleomycin,
doxorubicin, mitomycin
Carmustine, mitomycin, lomustine,
doxorubicin, gemcytidine.
Doxorubicin, methotrexate, cisplatin, combinations
for stomach
Methotrexate, mitomycin, carmustine,
cisplatin, floxuridine

Alpha interferon, progestins, infusional FUDR,
fluorouracil
Cyclophosphamide, fluorouracil

Bleomycin, vinblastine, ifosfamide,
mesna,2 carmustine, carboplatin

Ketoconazole, doxorubicin,
aminoglutethimide, progestins, cyclophosphamide,
cisplatin, estramustine, vinblastine, etoposide,
suramin1
Doxorubicin, cisplatin, fluorouracil, ifosfamide
Docetaxel, topotecan

Carboplatin, ifosfamide, lomustine

Mitoxantrone, vinblastine, paclitaxel,
docetaxel, topotecan, thiotepa, vincristine,
carboplatin, cisplatin/carboplatin, mitomycin,
vinorelbine, progestins, androgens, aminoglutethimide

Choriocarcinoma (trophoblastic neoplasms)3  Dose intensification or autologous bone marrow transplantation. Methotrexate or dactinomycin (or both) plus chlorambucil  Vinblastine, cisplatin, mercaptopurine, doxorubicin, bleomycin, etoposide
Carcinoma of the thyroid gland3 Carcinoma of the adrenal  Radioiodine (131I) Mitotane  Doxorubicin, cisplatin, bleomycin, melphalan Doxorubicin, suramin1
gland3 Carcinoid3 Osteogenic sarcoma3 Soft tissue sarcoma3 Melanoma3 Kaposi’s sarcoma Wilms’ tumor (in children)3 Neuroblastoma3  Fluorouracil plus streptozocin with or without alpha interferon High-dose methotrexate, doxorubicin, vincristine Doxorubicin, dacarbazine Dacarbazine, alpha interferon, IL-2 Vincristine alternating with vinblastine or vincristine alone. Palliative radiation therapy. Combination chemotherapy: vincristine and dactinomycin with or without doxorubicin after surgery and radiation therapy Combination chemotherapy: variations of cyclophosphamide, cisplatin, vincristine, doxorubicin, dacarbazine  Doxorubicin, cyclophosphamide, octreotide, cyproheptadine,2 methysergide2 Cyclophosphamide, ifosfamide, bleomycin, dacarbazine, cisplatin, dactinomycin Ifosfamide, cyclophosphamide, etoposide, cisplatin, high-dose methotrexate, vincristine Carmustine, lomustine, melphalan, thiotepa, cisplatin, paclitaxel,1 tamoxifen, vincristine Alpha interferon, bleomycin, etoposide doxorubicin Cyclophosphamide, methotrexate, etoposide, cisplatin Melphalan, ifosfamide, autologous or allogeneic bone marrow transplantation

1Investigational agent. Treatment is available through qualified investigators and centers authorized
by the National Cancer institute and Cooperative Oncology Groups.
2Supportive agent; not oncolytic.
3These tumors are generally managed initially with surgery with or without radiation therapy
with or without adjuvant chemotherapy. For metastatic disease, the role of palliative radiation
therapy is as important as that of chemotherapy.

Table 4–4 sets forth the currently used dosage schedules and toxicities of the most commonly used cancer chemotherapeutic agents.
The dosage schedules given are for single-agent therapy. Combination therapy is used for many diseases, including advanced-stage
Hodgkin's disease, non-Hodgkin's lymphoma, and testicular carcinoma. Hematologic or other toxicity may limit the therapeutic
effectiveness of chemotherapy. It is possible to avoid the need for dose reductions or delay in therapy by using granulocyte
colony-stimulating factor (G-CSF; filgrastim) or granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim).

Scroll right to see more columns.

Table 4–4. Single agent dosage and toxicity of anticancer drugs.
Drug Alkylating agents  Dosage  Acute Toxicity  Delayed Toxicity
Mechlorethamine  6–10 mg/m2 IV every 3  Severe vesicant; severe  Moderate suppression of blood counts.
weeks  nausea and vomiting  Melphalan effect may be delayed 4–6 weeks.
Excessive doses produce severe bone
marrow suppression with leukopenia,
Chlorambucil  0.1–0.2 mg/kg/d orally  None  thrombocytopenia, and bleeding.
(6–12 mg/d) or 0.4  Alopecia and hemorrhagic cystitis occur with
mg/kg pulse every 4  cyclophosphamide, while busulfan can cause
weeks  hyperpigmentation, pulmonary fibrosis, and
weakness (see text). Ifosfamide
Cyclophosphamide  100 mg/m2/d orally for  Nausea and vomiting with  is always given with mesna to prevent
14 days; 400 mg/m2  higher doses  cystitis. Acute leukemia may develop
orally for 5 days; 1–1.5  in 5–10% of patients receiving prolonged
g/m2 IV every 3–4 weeks  therapy with melphalan, mechlorethamine, or
chlorambucil; all alkylators probably increase
the risk of secondary malignancies with
prolonged use. Most cause either
Melphalan  0.25 mg/kg/d orally for 4  None  temporary or permanent aspermia/
days every 6 weeks  amenorrhea.
Busulfan  2–8 mg/d orally;  None
150–250 mg/course
Carmustine (BCNU)  200 mg/m2 IV every 6  Local irritant  Prolonged leukopenia and thrombocytopenia .
weeks  Rarely hepatitis. Acute leukemia has been
observed to occur in some patients
Lomustine (CCNU)  100–130 mg orally  Nausea and vomiting  receiving nitrosoureas. Nitrosoureas can
every 6–8 weeks  cause delayed pulmonary fibrosis with
prolonged use.
Procarbazine  100 mg/m2/d orally for  Nausea and vomiting  Bone marrow suppression, mental
14 days every 4 weeks  suppression, MAO inhibition, disulfiram-like
effect
Dacarbazine  250 mg/m2/d IV for 5  Severe nausea and  Bone marrow suppression; flu-like syndrome
days every 3 weeks;  vomiting; anorexia
1500 mg/m2 IV as
single dose

Cisplatin 50–100 mg/m2 IV every  Severe nausea and vomiting
3 weeks; 20 mg/m2 IV
for 5 days every 4 weeks
Carboplatin 360 mg/m2 IV every 4  Severe nausea and vomiting
weeks
Structural analogs or antimetabolites
Methotrexate 2.5–5 mg/d orally;  None
20–25 mg IM twice
weekly; high-dose:
500–1000 mg/m2 IV
every 2–3 weeks;
12–15 mg intrathecally
every week for 4–6
doses
Mercaptopurine 2.5 mg/kg/d orally; 100  None
mg/m2/d orally for 5
days for induction
Thioguanine 2 mg/kg/d orally; 100  Mild nausea, diarrhea
mg/m2/d IV for 7 days
for induction
Fluorouracil 15 mg/kg/d IV for 3–5  None
days every 3 weeks; 15
mg/kg weekly as
tolerated; 500–1000
mg/m2 IV every 4 weeks
Cytarabine 100–200 mg/m2/d for  High-dose: nausea,
5–10 days by  vomiting, diarrhea, anorexia
continuous IV infusion;
2–3 g/m2 IV every 12
hours for 3–7 days; 20
mg/m2 SC daily in
divided doses
Hormonal agents
Testosterone 100 mg IM 3 times  None
propionate weekly
Fluoxymesterone 20–40 mg/d orally  None
Flutamide 250 mg 3 times a day  None
orally
Diethylstilbestrol 1–5 mg/d orally in  Occasional nausea and
divided doses  vomiting
Ethinyl estradiol 3 mg/d orally  None
Tamoxifen 20 mg/d orally in 2  Transient flare of bone pain
divided doses
Megestrol acetate 40 mg orally 4 times daily  None
Anastrazole 1 mg orally daily  None
Hydroxyproges­1 g IM twice weekly  None
terone caproate
Medroxyproges­100–200 mg/d orally;  None
terone 200–600 mg orally twice
weekly
Adrenocorticosteroid
Prednisone 20–100 mg/d orally or  Alteration in mood
50–100 mg every other
day orally with systemic
chemotherapy
Aromatase inhibitor
Aminoglutethimide 500 mg/d orally, along  Initial drowsiness
with hydrocortisone, 40
mg/d orally
GnRH analogs
Leuprolide 7.5 mg IM (depot) once  Local irritation, transient
a month; 1 mg/d SC  flare of symptoms
Goserelin acetate 3.6 mg SC monthly  Transient flare of symptoms
Biologic response modifiers
Interferon alfa-2a 3–5 million units  Fever, chills, fatigue,
Interferon alfa-2b SC 3 times weekly or  anorexia
daily
Aldesleukin (IL-2) 600,000 IU/kg IV over  Hypotension, fever, chills,
15 minutes every 8  rigors, diarrhea, nausea,
hours for 14 doses,  vomiting, pruritus, liver,
repeated after 9-day  kidney, and CNS toxicity,
rest period. Some  capillary leak (primarily at
doses may be withheld  high doses), pruritic skin
or interrupted because  rash, infections (can be
of toxicity. Caution:  severe)
High doses must be
administered in an ICU
setting by experienced

Nephrotoxicity, mild otic and bone marrow
toxicity, neurotoxicity.

Bone marrow suppression, prolonged
anemia; same as cisplatin but milder.

Bone marrow suppression, oral and
gastrointestinal ulceration, acute renal failure;
hepatotoxicity, rash, increased toxicity when
effusions are present. Note: Citrovorum
factor (leucovorin) rescue for doses over 100
mg/m2.

Well tolerated. Larger doses cause bone
marrow suppression

Well tolerated. Larger doses cause bone
marrow suppression

Nausea, diarrhea, oral and gastrointestinal
ulceration, bone marrow suppression,
dacryocystitis.

Nausea and vomiting; cystitis; severe bone
marrow suppression; megaloblastosis; CNS
toxicity with high-dose cytarabine.

Fluid retention, masculinization, leg cramps.
Cholestatic jaundice in some patients
receiving fluoxymesterone.
Gynecomastia, hot flushes, decreased libido,
mild gastrointestinal side effects.
Fluid retention, feminization, uterine bleeding,
exacerbation of cardiovascular disease,
painful gynecomastia,
thromboembolic disease.
?Increased risk of venous thrombosis;
anovulation

Occasional fluid retention; rare thrombosis,
weight gain.

Fluid retention, hypertension, diabetes,
increased susceptibility to infection, "moon
facies," osteoporosis, electrolyte
abnormalities, gastritis.

Transient skin rash, which usually subsides
with continued therapy; weight gain, fluid
retention, leg cramps; cholestatic jaundice.

Hot flushes, decreased libido, impotence,
gynecomastia, mild gastrointestinal side effects
.

General malaise, weight loss, confusion

Hypoglycemia, anemia

personnel.
Peptide hormone inhibitor
Octreotide acetate  100–600 mg/d SC in 2  Local irritant; nausea and  Diarrhea, abdominal pain, hypoglycemia.
divided doses  vomiting
Natural products and miscellaneous agents
Vinblastine  0.1–0.2 mg/kg or 6  Mild nausea and vomiting;  Alopecia, peripheral neuropathy, bone
mg/m2 IV weekly  severe vesicant  marrow suppression, constipation, SIADH,
areflexia.
Vincristine  1.5 mg/m2 (maximum: 2  Severe vesicant  Areflexia, muscle weakness, peripheral
mg weekly)  neuropathy, paralytic ileus, alopecia (see
text), SIADH.
Vinorelbine  30 mg/m2 IV weekly  Mild nausea and vomiting,  Granulocytopenia, constipation, peripheral
fatigue, severe vesicant  neuropathy, alopecia
Paclitaxel  135 mg/m2 by  Hypersensitivity reaction  Peripheral neuropathy, bone marrow
continuous infusion over  (premedicate with  suppression, fluid retention.
24 hours every 3 weeks  diphenhydramine and
dexamethasone), mild
Docetaxel  60–100 mg/m2 IV every  nausea and vomiting
3 weeks
Dactinomycin  0.04 mg/kg IV weekly  Nausea and vomiting;  Alopecia, stomatitis, diarrhea, bone marrow
severe vesicant  suppression.
Daunorubicin  30–60 mg/m2 daily IV  Nausea, fever, red urine  Alopecia, stomatitis, bone marrow
for 3 days, or 30–60  (not hematuria); severe  suppression, late cardiotoxicity. Risk of
mg/m2 IV weekly  vesicant; acute cardiotoxicity  cardiotoxicity increases with radiation,
cyclophosphamide.
Idarubicin  12 mg/m2 daily IV for 3
days
Doxorubicin  60 mg/m2 IV every 3
weeks to a maximum
total dose of 550 mg/m2
Liposomal  20 mg/m2 IV every 3
Doxorubicin  weeks
Daunorubicin  40 mg/m2 IV every 2
weeks
Etoposide  100 mg/m2/d IV for 5  Nausea and vomiting;  Alopecia, bone marrow suppression.
days or 50–150 mg/d  occasionally hypotension
orally
Plicamycin  25–50 mg/kg IV every  Nausea and vomiting  Thrombocytopenia, diarrhea, hepatotoxicity,
(mithramycin)  other day for up to 8  nephrotoxicity, stomatitis.
doses
Mitomycin  10–20 mg/m2 every 6–8  Severe vesicant; nausea  Prolonged bone marrow suppression, rare
weeks  hemolytic-uremic syndrome.
Mitoxantrone  12–15 mg/m2/d IV for 3  Mild nausea and vomiting  Alopecia, mild mucositis, bone marrow
days with cytarabine;  suppression.
8–12 mg/m2 IV every 3
weeks
Bleomycin  Up to 15 units/m2 IM,  Allergic reactions, fever,  Fever, dermatitis, pulmonary fibrosis.
IV, or SC twice weekly  hypotension
to a total dose of 200
units/m2
Hydroxyurea  500–1500 mg/d orally  Mild nausea and vomiting  Hyperpigmentation, bone marrow
suppression.
Mitotane  6–12 g/d orally  Nausea and vomiting  Dermatitis, diarrhea, mental suppression,
muscle tremors.
Fludarabine  25 mg/m2/d IV for 5  Nausea and vomiting  Bone marrow suppression, diarrhea, mild
days every 4 weeks  hepatotoxicity, immune suppression.
Cladribine (CdA)  0.09 mg/kg/d by  Mild nausea, rash, fatigue  Bone marrow suppression, fever, immune
continuous IV infusion  suppression.
for 7 days
Topotecan  1.5 mg/kg IV daily for 5  Nausea, vomiting, diarrhea,  Alopecia, bone marrow suppression.
days every 3 weeks  headache, dyspnea
Tretinoin  45 g/m2 by mouth until  Retinoic acid syndrome (fever, dyspnea, pleural or pericardial effusion)
remission or for 90 days  must be treated emergently with dexamethasone; headache, dry skin rash,
flushing.
Gemcitabine  1000 mg/m2 every week  Nausea, vomiting, diarrhea,  Bone marrow suppression, rash, fluid
up to 7 weeks, then 1  fever, dyspnea  retention, mouth sores, flu-like symptoms,
week off, then weekly  paresthesias.
for 3 out of 4 weeks
Supportive agents
Allopurinol  300–900 mg/d orally for  None  Rash, Stevens-Johnson syndrome; enhances
prevention or relief of  effects and toxicity of mercaptopurine when
hyperuricemia  used in combination.
Mesna  20% of ifosfamide  Nausea, vomiting, diarrhea  None
dosage at the time of
ifosfamide
administration, then 4
and 8 hours after each
dose of chemotherapy
to prevent hemorrhagic

cystitis
Leucovorin  10 mg/m2 every 6 hours  None  Enhances toxic effects of fluorouracil.
IV or orally until serum
methotrexate levels are
below 5 ´ 10–8 mol/L
with hydration and
urinary alkalinization
(about 72 hours)
Amifostine  910 mg/m2 IV daily, 30  Hypotension, nausea,  Decrease in serum calcium.
minutes prior to  vomiting, flushing
chemotherapy
Dexrazoxane  10:1 ratio of  Pain on injection  Increased bone marrow suppression.
anthracycline IV, before
(within 30 minutes of)
chemotherapy infusion
Pilocarpine  5–10 mg orally 3 times  Sweating, headache, flushing; nausea, chills, rhinitis, dizziness, and
hydrochloride  daily  urinary frequency at high dosage
Pamidronate  90 mg IV every month  Symptomatic hypoglycemia  None
(rare), flare of bone pain,
local irritation
Epoetin alfa  100–300 units/kg IV or  Skin irritation or pain at  Hypertension, headache, seizures in
(erythropoietin)  SC 3 times a week  injection site  patients on dialysis (rare).
Filgrastim (G-CSF)  5 mg/kg/d SC or IV  Mild to moderate bone pain,  ?Unknown risk of tumor cell stimulation.
mild hypotension (rare),
irritation at injection sites
(rare)
Sargramostim  250 mg/kg/d as a 2-hour  Fluid retention, dyspnea,
(GM-CSF)  IV infusion (can be  capillary leak (rare),
given SC)  supraventricular tachycardia
(rare), mild to moderate
bone pain, irritation at
injection sites

Hormonal therapy also plays an important role in cancer management. Hormonal therapy or ablation is important in treatment and palliation of breast and prostatic carcinoma, while added progestins are useful in suppression of endometrial carcinoma. Women with metastatic breast cancer who show objective improvement with hormonal therapy have tumors that contain cytoplasmic estrogen and progesterone receptors. Antiestrogens (eg, tamoxifen) and aromatase inhibitors (eg, anastrazole or megestrol acetate) that block peripheral conversion of adrenal androgens into estrogens have substantial additive effects to—or may obviate the need for—oophorectomy in premenopausal women whose tumors are estrogen- or progesterone receptor-positive. Hormonal approaches are also available to treat prostate cancer, though androgen receptors remain difficult to measure. These include the use of estrogen therapy, gonadotropin-releasing hormone agonists (eg, leuprolide), aromatase inhibitors (eg, aminoglutethimide), and antiandrogens (eg, flutamide). The use of leuprolide plus flutamide can be considered as an alternative to orchiectomy but also causes impotence. High-dose ketoconazole has been used to rapidly suppress adrenal production of steroids in crises such as cord compression. Use of this agent requires hydrocortisone supplementation. Several recombinant growth factors have been shown to be effective in the treatment of malignancy. Recombinant alpha interferon has marked antitumor effects in hairy cell leukemia and chronic myelogenous leukemia, moderate effects in lymphomas, in the epidemic (AIDS-associated) form of Kaposi's sarcoma, in multiple myeloma, and as adjuvant therapy for malignant melanoma. Alpha interferon has some utility also in metastatic melanoma, renal cell carcinoma, and carcinoid syndrome. Patients with chronic myelogenous leukemia may benefit from treatment with alpha interferon and achieve both a hematologic and cytogenetic remission. Patients with a cytogenetic response to interferon (about 30% of treated patients) have longer survival than patients treated with standard oral chemotherapy. The addition of alpha interferon to systemic chemotherapy for multiple myeloma appears to enhance the degree of cytoreduction achieved as compared with chemotherapy alone; toxicity is additive. Use of alpha interferon for myeloma following chemotherapy or autologous bone marrow transplant has prolonged remission duration, though overall survival may not be altered. Another cytokine, interleukin-2, when administered alone or in combination with lymphocyte-activated killer cells or tumor-infiltrating lymphocytes, exhibits marked antitumor activity in a minority of patients with melanoma or renal cancer, though its use is associated with marked toxicity. In addition to cytokines, other agents have recently been shown to be efficacious in the treatment of some tumors. For chronic lymphocytic leukemia and low-grade lymphomas, fludarabine phosphate, cladribine (2-chlorodeoxyadenosine; CdA), and pentostatin (2-deoxycoformycin) are effective. Studies using cladribine to treat hairy cell leukemia have resulted in a high remission rate that is durable with tolerable toxicities after a 1-week course of therapy. Pentostatin has been approved for use in hairy cell leukemia. Paclitaxel is a novel agent isolated from the Pacific yew tree that has been found to be effective in reducing tumor size in 20–35% of patients with refractory metastatic ovarian cancer, though most patients experienced rapid disease progression after an initial response; paclitaxel combined with carboplatin appears to be more effective than cyclophosphamide plus carboplatin in the adjuvant setting. Dose intensification as well as intraperitoneal instillation may also be helpful. The toxicity of paclitaxel is primarily hematologic and neurologic. The hematologic toxicity is dose-dependent and can be ameliorated by the use of myeloid growth factors. Effectiveness has been demonstrated in metastatic carcinoma of the breast as well as in other cancers. Docetaxel, a synthetic analog of paclitaxel, has recently been approved and is effective also in the treatment of advanced malignancies, especially breast cancer. Toxicities are similar to those of paclitaxel. Vinorelbine, a semisynthetic vinca alkaloid, has recently been approved for use in treating advanced non-small-cell lung cancer. Response rates of 30% have been observed when vinorelbine is used as a single agent in this poorly responsive tumor. Current studies are evaluating combination chemotherapy, including vinorelbine, in the treatment of metastatic breast cancer and other tumors. Newer experimental cancer therapies are discussed briefly at the end of this chapter.
 10040:7:1 Berkowitz RS, Goldstein DP: Chorionic tumors. N Engl J Med 1996;335:1740. (Review of the clinical presentation and treatment of this curable tumor.)
 10040:7:2 Chabner BA: Biological basis for cancer treatment. Ann Intern Med 1993;118:633. (A discussion of cancer biology as the basis of drug discovery research and a review of novel cancer therapies.)
 10040:7:3 O'Brien S, del Giglio A, Keating M: Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 1995;85:307. (Fludarabine treatment results in high complete remission rates and may allow more aggressive subsequent therapy.)
 10040:7:4 Philip T et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995;333:1540. (Bone marrow transplantation for chemotherapy-sensitive relapsed lymphoma markedly improves event-free survival over standard salvage chemotherapy [46% versus 12% at 5 years].)
 10040:7:5 Pritchard RS, Anthony SP: Chemotherapy plus radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer: A meta-analysis. Ann Intern Med 1996;125:723. (Fourteen articles with 2589 patients suggested a 2-month mean gain in life expectancy when chemotherapy was added to radiation therapy.)
 10040:7:6 Rowinsky EK, Donehower RC: Paclitaxel (Taxol). N Engl J Med 1995;332:1004. (A thorough review, including mechanisms of action, toxicity, and antitumor effects.)
 10040:7:7 Saven A, Piro LD: Treatment of hairy cell leukemia. Blood 1992;79:1111. (Current and investigational treatments of hairy cell leukemia, including interferon, deoxycoformycin, and cladribine.)
 10040:7:8 Yuen A, Sikic BI: Multidrug resistance in lymphomas. J Clin Oncol 1994;12:2453. (Review of multidrug resistance in lymphomas and status of ongoing trials using modulating agents.)


Adjuvant Chemotherapy for Micrometastases
One of the most important roles of cancer chemotherapy is as adjuvant therapy to eradicate or suppress minimal residual disease after primary field treatment with surgery or irradiation. Failure of primary field therapy to eradicate tumor is due principally to occult micrometastases of tumor stem cells outside the primary field. These distant micrometastases are more likely to be present in patients with positive lymph nodes at the time of surgery (eg, breast cancer), in patients with tumors known to have a propensity for early hematogenous spread (eg, osteogenic sarcoma, Wilms' tumor), and in patients with certain pathologic or molecular risk factors (eg, high proliferative index, vascular invasion, oncogene amplification). Given specific risk factors, the risk of recurrent or metastatic disease can be extremely high (> 80%). Only systemic therapy can adequately prevent micrometastases. Chemotherapeutic regimens that have been shown to be effective in inducing regression of advanced cancers may be curative when combined with surgery for high-risk "early" cancer. More data are now available to support the use of adjuvant therapy in several neoplasms. Prolongation of survival times has been shown for women (especially premenopausal women) with breast cancer and positive or negative axillary lymph nodes (stages I, II, and III) from combination chemotherapy following surgical resection; there are several useful regimens. Node-negative patients are treated with CMF (cyclophosphamide, methotrexate, and fluorouracil) or variants, whereas high-risk, node-positive patients are generally treated with regimens that include doxorubicin. Neoadjuvant (preoperative) and perioperative chemotherapy are also used and may improve surgical resectability or time to disease progression. The antiestrogen tamoxifen is used routinely either with or without antecedent chemotherapy if receptors for estrogen and progesterone are present. The role of amplification of the c-erbB-2 or Her-2/neu oncogene in tamoxifen-resistant breast cancer is a subject of current research. In postmenopausal women, tamoxifen alone may be used. The main challenge in treating women with node-negative (stage I) breast cancer is to identify prognostic factors to determine which patients are at higher risk and therefore more likely to benefit from adjuvant therapy. Adjuvant chemotherapy with fluorouracil plus levamisole is now indicated in Dukes C (node-positive) colon cancer and has been shown to reduce the risk of cancer recurrence. Earlier clinical trials employing semustine (methyl-CCNU) appeared to result in an increased risk of both leukemia and renal insufficiency. The omission of semustine from combination regimens still results in enhanced cure rates with decreased local and overall tumor recurrence. Other tumors that have been shown to respond to adjuvant therapy include osteogenic sarcoma, ovarian cancer, and malignant melanoma. Adjuvant therapy remains investigational and unproved for a number of common tumors, including non-small-cell lung cancer and pancreatic cancer. Patients with Hodgkin's disease or testicular carcinoma do not benefit from adjuvant therapy. Although adjuvant therapy has been shown to reduce the rate of recurrence for some cancers, there is still a high failure rate (up to 80% in high-risk breast cancer despite adjuvant therapy). In most cases, tumor recurrence signifies incurability. There is clear evidence of a dose-response effect of adjuvant chemotherapy in some cancers; however, doses have been limited by bone marrow toxicity. Current studies are investigating the use of dose-intense chemotherapy regimens with or without autologous bone marrow or peripheral blood progenitor cell rescue in the high-risk adjuvant setting for patients with carcinoma of the breast, testis, and ovaries. Otherwise incurable patients with testicular cancer have been cured by this intensive treatment approach. Nonrandomized studies suggest efficacy with tolerable side effects of high-dose chemotherapy with stem cell support in the setting of high-risk breast cancer (more than ten positive lymph nodes). Multicenter trials are now in progress comparing aggressive adjuvant chemotherapy with autologous bone marrow transplantation for high-risk breast cancer. The use of marrow transplantation for high-risk ovarian cancer remains controversial, though long-lived responses in otherwise incurable patients have been documented. Patients with advanced ovarian cancer at high risk for recurrence may now be considered for treatment in a multicenter randomized study comparing transplantation with standard adjuvant chemotherapy. Young patients with high-risk malignancies should be considered for entry into clinical trials investigating this aggressive, potentially curable therapy. 10040:8:1 [Physicians' Data query: Information on cancer treatment] http://cancernet.nci.nih.gov/h_treat.htm
 10040:8:2 Bonadonna G et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 1995;332:901. (Long-term improvement in survival in patients with node-positive breast cancer randomized to receive adjuvant chemotherapy following mastectomy.)
 10040:8:3 Cannistra SA: Cancer of the ovary. N Engl J Med 1993;329:1550. (A review of risk factors, presentation, staging, surgical treatment and chemotherapy, and prognosis.)
 10040:8:4 Gradishar WJ, Tallman MF, Abrams JS: High-dose chemotherapy for breast cancer. Ann Intern Med 1996;125:599. (A review of this controversial but widely used therapy.)
 10040:8:5 Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 1994;330:1136.
 10040:8:6 Trimble EL et al: Neoadjuvant therapy in cancer treatment. Cancer 1993;72:3515. (Increasing indications.)

Toxicity and Dose Modification of Chemotherapeutic Agents
A number of cancer chemotherapeutic agents have cytotoxic effects on rapidly proliferating normal cells in bone marrow, mucosa, and skin. Still other drugs such as the vinca alkaloids produce neuropathy, and hormones often have psychologic effects. Acute and chronic toxicities of the various drugs are summarized in Table 4–4. Appropriate dose modification usually minimizes these side effects, so that therapy can be continued with relative safety.
Bone Marrow Toxicity
Depression of bone marrow is usually the most serious limiting toxicity of cancer chemotherapy. Autologous bone marrow or peripheral blood progenitor cell transplantation or rescue can reduce the myelosuppressive toxicity of high-dose chemotherapy; however, cost and toxicity limit its general use. Growth factors that stimulate myeloid proliferation (eg, granulocyte colony-stimulating factor [G-CSF; filgrastim] and granulocyte-macrophage stimulating factor [GM-CSF]; sargramostim) or erythroid proliferation (erythropoietin [epoetin alfa]) are now used to ameliorate bone marrow toxicity. G-CSF and GM-CSF have been shown to shorten the period of neutropenia following both standard and high-dose chemotherapy. Mucosal toxicity is also reduced. The myeloid growth factors are also used to stimulate circulation of progenitor cells in the peripheral blood either at steady state or during white blood cell recovery following myelosuppressive chemotherapy. These cells are then harvested using an apheresis machine and frozen for later use. When stimulated peripheral blood progenitor cells are used instead of or in conjunction with bone marrow for autologous transplantation following high-dose chemotherapy and radiotherapy, recovery of both neutrophils and platelets may be hastened by as much as 7–10 days as opposed to the use of bone marrow alone. Epoetin alfa (erythropoietin) has been shown to improve anemia associated with malignancy. Patients must have adequate iron stores to respond to this agent, and even patients with marrow infiltration with tumor may benefit. Higher doses are necessary for patients with cancer than for patients with renal failure (100–150 units/kg compared with 50 units/kg). It is useful to check the level of erythropoietin before instituting therapy. Very high levels (> 500 ng/mL) predict a poor response. Erythropoietin is usually given by subcutaneous injection three times a week. Thrombocytopenia remains a problem with high doses of or prolonged exposure to chemotherapeutic agents and may limit therapy. Several agents may help with this problem. Interleukin-3 stimulates myeloid growth and, to a lesser extent, platelet recovery. The megakaryocyte growth factor thrombopoietin has been cloned and is the subject of intense study. Clinical trials using thrombopoietin in a variety of circumstances are under way. Commonly used short-acting drugs that affect the bone marrow are the alkylating agents (eg, cyclophosphamide, melphalan, chlorambucil), procarbazine, mercaptopurine, methotrexate, vinblastine, fluorouracil, dactinomycin, and doxorubicin. In general, it is preferable to use alkylating agents in intensive "pulse" courses every 3–4 weeks rather than to administer the drugs in continuous daily schedules. This allows for complete hematologic (and immunologic) recovery between courses rather than continuously suppressing the bone marrow with a cytotoxic agent. Pulse therapy reduces side effects to some degree but does not reduce therapeutic efficacy. The standard dosage schedules required to produce tumor responses with these agents often induce bone marrow depression. Continuing some drugs in the face of falling blood counts may result in severe bone marrow aplasia with pancytopenia, bleeding, or infection. Simple guidelines for treatment and follow-up can usually prevent severe marrow depression. With long-term chemotherapy, counts should be obtained initially at weekly intervals; the frequency of counts may be reduced only after the patient's sensitivity to the drug can be well predicted (eg, 3–4 months) and cumulative toxicity excluded. In patients with normal blood counts as well as normal liver and kidney function, drugs should be started in full dosages. Bone marrow toxicity is cumulative over time, and this must be anticipated during follow-up. Patients with bone marrow involvement may tolerate chemotherapy poorly initially, with improved counts on future cycles as the tumor burden is reduced. Drug dosage can usually be modified as a function of the peripheral white blood count or platelet count (or both). These modifications assume that the blood counts are checked shortly before the next course of chemotherapy is to be administered. Dosage modifications are used primarily for repeated courses of oral alkylator or antimetabolite therapy but should be avoided when possible if treatment is given with curative intent. A scheme for dosage modification is presented in Table 4–5. Alternatively, the interval between drug courses can be lengthened, thereby permitting more complete hematologic recovery and repetition of full-dose chemotherapy. Both dosage modification and delay of chemotherapy limit the efficacy of treatment.

Table 4–5. A common scheme for dose modification of cancer chemotherapeutic agents.1
Granulocyte Suggested Drug
Count Platelet Count (/mL) Dosage (% of full dose)
> 2000/µL > 100,000/µL 100%
1000–2000/µL 75,000–100,000/µL 50%
< 1000/µL < 50,000/µL 0% 1In general, dose modification should be avoided if full recovery is expected within 1–2 weeks. Chemotherapy can be delayed and given after recovery at full dosage to maintain therapeutic efficacy.
 10040:9:1 ASCO Ad Hoc Colony-Stimulating Factor Guideline Expert Panel: American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based clinical practice guidelines. J Clin Oncol 1994;12:2471. (Standard practice guidelines.)
 10040:9:2 Kaushansky K: Thrombopoietin: The primary regulator of megakaryocyte and platelet production. Thromb Haemost 1995;74:521. (A review of current preclinical data.)
 10040:9:3 Vose JM, Armitage JO: Clinical applications of hematopoietic growth factors. J Clin Oncol 1995;13:1023.

Chemotherapy-Induced Nausea & Vomiting
A number of cytotoxic anticancer drugs induce nausea and vomiting. In general, these symptoms are thought to originate in the central nervous system rather than peripherally. Parenteral administration of agents such as doxorubicin, etoposide, or cyclophosphamide frequently is associated with mild to moderate nausea and vomiting, whereas nitrosoureas, dacarbazine, and particularly cisplatin usually cause severe symptoms. Combination chemotherapy can also cause severe symptoms. Antiemetics clearly reduce and often eliminate nausea and vomiting associated with these drugs and are especially useful in conjunction with cisplatin. Metoclopramide is a particularly useful agent, especially when administered parenterally at a dosage of 1–2 mg/kg both 30 minutes before and again 30 minutes after the administration of chemotherapy. Extrapyramidal signs may be induced with this drug but frequently can be suppressed with 25–50 mg of oral or parenteral diphenhydramine. Dexamethasone has antiemetic effects when administered at a dosage of 6–10 mg either as a single dose prior to or both prior to and every 6 hours following the administration of chemotherapy for two to four total doses. Both of these drugs are more potent than conventional agents such as prochlorperazine, diphenhydramine, and thiethylperazine. Prochlorperazine is given at a dose of 10 mg orally or intravenously every 6 hours. The total dose given over 24 hours should not exceed 40 mg. A 25 mg rectal suppository is available and may be useful for patients who are too nauseated to swallow pills without experiencing further emesis. Unfortunately, all phenothiazines can induce extrapyramidal side effects. Thiethylperazine is given at a dose of 10 mg every 8 hours by mouth and is also available at the same dose in a rectal suppository. Lorazepam has both antiemetic and sedating effects and is administered at a dose of 0.5–1 mg every 4–6 hours by the sublingual route, making it particularly useful in the outpatient setting. Older patients may have intolerable psychologic side effects. Combinations of antiemetics (eg, metoclopramide with dexamethasone and lorazepam) are often more effective than maximal doses of any one agent for blocking cisplatin-induced vomiting. 5-Hydroxytryptamine-3 receptor antagonists (ondansetron, granisetron) have now replaced high-dose metoclopramide in the treatment and prevention of emesis. A new and very potent class of antiemetics, these drugs are serotonin receptor-blocking agents that have few side effects. They are both more effective and less toxic than metoclopramide in cisplatin-treated patients. They are also effective against radiation-induced and postanesthetic vomiting as well as for patients with refractory nausea and vomiting following administration of other chemotherapeutic agents. Ondansetron is administered by the parenteral route at a dose of 0.15 mg/kg for three doses or orally at a dose of 8 mg every 8 hours. The first dose is given 30 minutes before the start of chemotherapy; subsequent doses are given 4 and 8 hours after the first dose. A typical antiemetic regimen might include ondansetron combined with 0.5–1 mg of lorazepam (sublingual) or 10 mg of prochlorperazine orally or intravenously and dexamethasone (10 mg orally), omitting both metoclopramide and diphenhydramine. For less emetogenic regimens, ondansetron alone may be no more effective than metoclopramide and dexamethasone and is usually used only for failure to control nausea with less expensive combination regimens. Granisetron is a long-acting serotonin receptor antagonist that is given as a single dose of 10 mg/kg intravenously 30 minutes before chemotherapy or orally at a dosage of 1–2 mg/d. The half-life of granisetron is 9 hours, and 24-hour dosing is recommended by the manufacturer. Ondansetron may also be effective in a single daily parenteral dose of 32 mg. Both agents appear to be more effective when given in conjunction with dexamethasone. Dronabinol (D9-tetrahydrocannabinol) is effective in some patients at a dose of 5 mg/m2 prior to and then every 2–4 hours following chemotherapy for a total of four to six doses a day. Dronabinol may cause undesirable side effects such as dysphoria, and it is available only for oral administration. A patient receiving antiemetics (eg, lorazepam, prochlorperazine, metoclopramide) along with chemotherapy on an outpatient basis must be escorted to and from the clinic, since the antiemetics often induce marked sedation and transient impairment of balance and reflexes. Antiemetics are more effective when given prophylactically. Therefore, regular dosing of an agent such as lorazepam or prochlorperazine is recommended after chemotherapy until the emetogenic effects have dissipated. This is dependent on the patient as well as on the type of chemotherapy administered. One problem with all combinations of antiemetic agents is the development of tachyphylaxis over 4–5 days with continuing highly emetogenic chemotherapy. This limits the effectiveness of any regimen.
 10040:10:1 Grunberg SM et al: Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790. (Mechanisms and treatment.)
 10040:10:2 Perez EA: Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis. J Clin Oncol 1995;13:1036. (This is a highly effective class of antiemetic agents, and all three studied appear to be relatively equivalent.)

Gastrointestinal & Skin Toxicity
Since antimetabolites such as methotrexate and fluorouracil act only on rapidly proliferating cells, they damage the cells of mucosal surfaces such as the gastrointestinal tract. Methotrexate has similar effects on the skin. These toxicities are at times more serious than bone marrow suppression, and they should be looked for routinely when these agents are used. Erythema of the buccal mucosa is an early sign of mucosal toxicity. If therapy is continued beyond this point, oral ulceration will develop. In general, it is wise to discontinue therapy at the time of appearance of early oral ulceration. This finding usually heralds the appearance of similar but potentially more serious ulceration at other sites lower in the gastrointestinal tract. Therapy can usually be reinstituted when the oral ulcer heals (7–10 days). The dose of drug used may need to be modified downward at this point, with titration to an acceptable level of mucosal toxicity. Adequate mouth care with antimicrobial mouthwashes and attention to dental hygiene are essential and may prevent severe toxicity. Common mouthwashes include the microbicidal oral rinse chlorhexidine and a mixture of salt and bicarbonate of soda in warm water, which aids in debridement of dead mucosa. A prophylactic antifungal mouthwash such as nystatin oral suspension may also be used. High doses of methotrexate require special consideration as noted in the following section. Radiation therapy may cause xerostomia, which can lead to difficulty in swallowing, discomfort, and gum disease. Pilocarpine hydrochloride, 5–10 mg orally three times a day, can relieve symptoms of dry mouth but must be used regularly.

Miscellaneous Drug-Specific Toxicities
The toxicities of individual drugs have been summarized in Table 4–4. Several of these warrant additional mention, since they occur with commonly administered agents, and special preventive measures are often indicated.
A. Hemorrhagic Cystitis Induced by Cyclophosphamide or Ifosfamide: Metabolic products of cyclophosphamide that retain cytotoxic activity are excreted into the urine. Some patients appear to metabolize more of the drug to these active excretory products. If their urine is concentrated, the toxic metabolite may cause severe bladder damage. Patients receiving cyclophosphamide must be advised to maintain a high fluid intake. Early symptoms of bladder toxicity include dysuria and frequency despite the absence of bacteriuria. Such symptoms develop in about 20% of patients who receive the drug chronically. If microscopic hematuria develops, it is advisable to stop the drug temporarily or switch to a different alkylating agent, increase fluid intake, and administer a urinary analgesic such as phenazopyridine. With severe cystitis, large segments of bladder mucosa may be shed and the patient may have prolonged gross hematuria. Such patients should be observed for signs of urinary obstruction and may require cystoscopy for removal of obstructing blood clots. The risk of developing hemorrhagic cystitis is dose-related. For high doses of cyclophosphamide, preventive continuous bladder irrigation with 0.9% saline solution is used during the period of drug administration and for the following 24 hours. The cyclophosphamide analog ifosfamide can cause severe hemorrhagic cystitis when used alone. However, when it is used in conjunction with a series of doses of the neutralizing agent mesna, bladder toxicity can be prevented. Mesna can also be used to prevent cystitis in patients receiving cyclophosphamide in high doses.
B. Vincristine-Induced Neuropathy: Neuropathy is a toxic side effect that is peculiar to the vinca alkaloid drugs, especially vincristine. The peripheral neuropathy can be sensory, motor, autonomic, or a combination of these effects. In its mildest form, it consists of paresthesias of the fingers and toes. Occasional patients develop acute jaw or throat pain after vincristine therapy. This may be a form of trigeminal or glossopharyngeal neuralgia. With continued vincristine therapy, the paresthesias may extend to the proximal interphalangeal joints, hyporeflexia can appear in the lower extremities, and weakness may develop in the quadriceps muscle group. At this point, it is wise to discontinue vincristine therapy until the neuropathy has subsided. A useful means of judging whether peripheral motor neuropathy is severe enough to warrant stopping treatment is to have the patient attempt to do deep knee bends or rise from a chair without using the arm muscles. Constipation is the most common symptom of autonomic neuropathy associated with vincristine therapy. Patients receiving vincristine should be started on stool softeners and mild cathartics when therapy is begun; otherwise, severe impaction may result along with an atonic bowel. More serious autonomic involvement can lead to acute intestinal ileus with signs indistinguishable from those of an acute abdomen. Bladder neuropathies are uncommon but may be severe. These two complications are absolute contraindications to continued vincristine therapy. The majority of symptoms from vincristine are mild and resolve slowly after therapy has been completed. Paclitaxel, cisplatin, carboplatin, and vinorelbine can also cause peripheral neuropathy, though as a rule symptoms improve gradually after treatment is stopped.
C. Methotrexate Toxicity and Citrovorum Rescue: In addition to standard uses of methotrexate for cancer chemotherapy, this drug is also used in very high doses that could lead to fatal bone marrow toxicity if given without an antidote. High-dose methotrexate therapy with leucovorin rescue is routinely used to treat osteogenic sarcoma, acute lymphocytic leukemia, and some cases of non-Hodgkin's lymphoma. The bone marrow and mucosal toxicity of methotrexate can be prevented by early administration of leucovorin. Serum levels of methotrexate are usually monitored and doses of leucovorin adjusted accordingly. Rescue is required for methotrexate doses over 80 mg/m2 and is usually begun within 4 hours after completing treatment. Up to 100 mg/m2 of leucovorin is given initially every 6 hours, with further doses adjusted for the serum methotrexate level. Rescue is usually continued orally for 3 days or longer until the serum methotrexate level is below 0.05 mmol/L. If an overdose of methotrexate is administered accidentally, leucovorin therapy should be initiated as soon as possible, preferably within 1 hour. Intravenous infusion should be employed for larger overdosages to ensure adequate drug delivery. It is generally advisable to give leucovorin repeatedly in this situation. Vigorous hydration and bicarbonate loading also appear to be important in preventing crystallization of high-dose methotrexate in the renal tubular epithelium. Serum creatinine is determined before beginning therapy and daily thereafter, since methotrexate excretion is slowed by renal insufficiency and toxicity will be enhanced. In high doses, methotrexate can itself cause renal injury. Methotrexate doses are reduced in renal insufficiency. Concomitant use of certain drugs will slow methotrexate excretion, and they are avoided during therapy. These drugs include aspirin, NSAIDs, penicillins, sulfonamides, and probenecid.
D. Busulfan Toxicity: The alkylating agent busulfan, occasionally used for the treatment of chronic myelogenous leukemia, has curious delayed toxicities, including increased skin pigmentation, a wasting syndrome similar to that seen in adrenal insufficiency, and progressive pulmonary fibrosis. Patients who develop either of the latter two problems should be switched to a different drug (eg, melphalan) when further therapy is needed. The pigmentary changes are innocuous and will usually regress slowly after treatment is discontinued. Long-term treatment with busulfan also results in an increased risk of secondary leukemias.
E. Bleomycin Toxicity: This antibiotic has found increasing application in cancer chemotherapy in view of its activity in squamous cell carcinomas, Hodgkin's disease, non-Hodgkin's lymphomas, and testicular tumors. Bleomycin can produce edema of the interphalangeal joints and hardening of the palmar and plantar skin. More serious toxicities include an anaphylactic or serum sickness-like reaction and a potentially fatal pulmonary fibrotic reaction (seen especially in elderly patients receiving a total dose of over 300 units). If a nonproductive cough, dyspnea, and pulmonary infiltrates develop, the drug is discontinued, and high-dose corticosteroids are instituted as well as empiric antibiotics pending cultures. Fever alone or with chills is an occasional complication of bleomycin treatment and is not an absolute contraindication to continued treatment. The fever may be avoided by hydrocortisone administration just prior to the injection. Fever alone is not predictive of pulmonary toxicity. About 1% of patients (especially those with lymphoma) may have a severe or even fatal hypotensive reaction after the initial dose of bleomycin. In order to identify and treat such patients, it is wise to administer a test dose of 5 units of bleomycin first and to have adequate monitoring and emergency facilities available. Patients exhibiting a hypotensive reaction should not receive further bleomycin therapy.
F. Doxorubicin-Induced Cardiomyopathy: The anthracycline antibiotics doxorubicin and daunomycin both have acute and delayed cardiac toxicity. The problem is greater with doxorubicin because it has a major role and is used in repeated doses in the treatment of sarcomas, breast cancer, lymphomas, acute leukemia, and certain other solid tumors. Studies of left ventricular function and endomyocardial biopsies indicate that some changes in cardiac dynamics occur in most patients by the time they have received 300 mg/m2 of doxorubicin. The multiple-gated ("MUGA") radionuclide cardiac scan is the most useful noninvasive test for assessing toxicity. Doxorubicin should not be used in elderly patients with intrinsic cardiac disease. In general, patients should not receive a total dose in excess of 550 mg/m2, and 1–10% of patients who receive this dose develop cardiomyopathy. Patients who have had prior chest or mediastinal radiotherapy may develop doxorubicin heart disease at lower total doses. The appearance of a high resting pulse may herald the appearance of cardiac toxicity. Unfortunately, the toxicity may be irreversible and frequently fatal at dosage levels above 550 mg/m2. At lower doses (eg, 350 mg/m2), the symptoms and signs of cardiac failure generally respond well to digitalis, diuretics, and cessation of doxorubicin therapy. Recent evidence suggests that cardiac toxicity can be correlated with high peak plasma levels obtained with intermittent high-dose bolus therapy (eg, every 3–4 weeks). Use of weekly injections or low-dose continuous infusion schedules appears to delay the occurrence of cardiac toxicity. Current laboratory studies suggest that cardiac toxicity may be due to a mechanism involving the formation of intracellular free radicals in cardiac muscle. Pretreatment with dexrazoxane, an iron chelator that decreases free radical formation, appears to protect the myocardium from anthracycline-induced injury but may also reduce the anticancer efficacy of the anthracycline. Dexrazoxane is now approved for the prevention of cardiomyopathy in women with metastatic breast cancer receiving cumulative doxorubicin doses > 300 mg/m2. Liposomally encapsulated doxorubicin and daunorubicin have been FDA-approved and appear to have minimal cardiac toxicity. Their main use to date has been to treat Kaposi's sarcoma. Newer anthracycline analogs include idarubicin, which has shown efficacy against acute nonlymphocytic leukemia and breast cancer when used in combination with other agents. Idarubicin appears to have a similar potential for causing cardiotoxicity when compared with other anthracyclines, though a maximum lifetime dosage recommendation has not yet been made.
G. Cisplatin Nephrotoxicity and Neurotoxicity: Cisplatin is effective in the treatment of testicular, bladder, and ovarian cancer as well as in several other types of tumor. Nausea and vomiting are common, but nephrotoxicity and neurotoxicity are more serious. Vigorous hydration with or without mannitol diuresis may substantially reduce nephrotoxicity. Renal function must be carefully monitored during cisplatin therapy, as should serum magnesium, which may fall during therapy with this agent. Ototoxicity is a potentially serious neurotoxicity that can result in deafness. The neurotoxicity of this drug is delayed and is more common after a total dose of 300 mg/m2. Other manifestations include peripheral neuropathy of mixed sensorimotor type that may be associated with painful paresthesias. These supportive measures do not appear to reduce the therapeutic effectiveness of cisplatin. The second-generation platinum analog carboplatin is now available and has been shown to be as effective as cisplatin in ovarian cancer. Carboplatin is less nephrotoxic and causes less severe nausea or vomiting, but it does induce myelosuppression. Amifostine, an organic thiophosphate initially developed as a radioprotective agent, has efficacy in preventing renal toxicity from cisplatin. It has recently been approved to reduce cumulative renal toxicity associated with repeat administration of cisplatin in advanced ovarian cancer. In addition, amifostine may reduce cytotoxic chemotherapy-induced hematologic toxicity and neurotoxicity. Glutathione also appears to be a promising agent in preventing cisplatin neurotoxicity. Glutathione was given at a dose of 1.5 g/m2 intravenously before cisplatin administration, then at a dose of 600 mg by intramuscular injection on days 2–5.
H. Alpha Interferon Toxicities: While alpha interferon is generally tolerated in the standard doses listed in Table 4–4, it has increasing toxicity with increasing doses and is more toxic in elderly patients. Even standard doses may be intolerable to some patients. Fever and chills are initial side effects but are infrequent after continued treatment. These symptoms may be ameliorated or prevented by premedication with acetaminophen and bedtime dosing. However, anorexia, fatigue, and weight loss can be cumulative and with time may become severe. These symptoms may be dose- or treatment-limiting. Thirty percent or more of patients are intolerant of interferon therapy even at low doses. In some patients, central nervous system symptoms develop, usually manifested as confusion or somnolence. Reduction in peripheral blood counts can develop, but this abnormality is usually not clinically important and may even be a desired effect in the treatment of chronic myelogenous leukemia. These interferon-induced side effects are sometimes confused with the symptoms of progressive cancer. The side effects usually clear within 1 week after cessation of interferon therapy.

Bone and Joint Infections

1
Bone and Joint Infections
Janet Wong, M.D.

2
Acute Osteomyelitis - Microbial Etiology
Neonate Infant Older Chid
Group B streptococcus
S. aureus
Candida sp.
Enterobacteriaceae
other streptococci
S. aureus
S. pyogenes
S. pneumoniae
H. influenzae
S. aureus
S. pyogenes
Salmonella (SSA)
There are three different routes of infection in children. The most
common seems to be the hematogenesis route, which gains
entry into the bone from the blood stream. Less commonly is by
direct inoculation and this can be a puncture wound, such as
stepping on a nail or something. This can also occur following
trauma or surgery. Finally, a particular spread, which is really
rare in children and seems to be more common in adults with
various disabilities, especially alterations in blood flow.

3
Unusual Organisms and Osteomyelitis
. Penetrating trauma: soil organisms, yeast, gram negative
. Hemoglobinopathies: salmonella
. Brucella: sacroiliitis
. IV drug abuse: P. aeruginosa
. Chronic Osteomyelitis: Gram negative enteric, Staphylococcus
. Fractures, surgery: chronic osteomyelitis
. Contiguous Infection: anaerobes (bite, ulcer, sinusitis, mastoiditis)
. Fungi: disseminated H. capsulatum, C. immitis
What is thought to happen from the hematogenesis standpoint is
that the during a course of bacteremia, as the organisms enter
into the bone through the nutrient artery towards the growth
plate, there are these loose capillaries that are said to have
sluggish blood flow in them. It is also thought that maybe there is
a fully developed reticulum within this system. There does seem
to be evidence of low oxygen within the metaphysis, and we
always hear about this preceding history of trauma as a possibly
predisposing factor. Perhaps this is simply disruptive blood flow,
but the history of trauma to children is common, and it is hard to
know what really this is contributing to the pathogenesis.
The nutrient artery penetrates into the diaphysis of the bone,
moving up into the metaphysis and making a hairpin turn at the
epiphysis. This is why it is in a long individual, at least for the
tubular long bones, that osteomyelitis is more common at the
ends of the bones because of these here hairpin turns.
More recently there is some evidence in animals, specifically
chickens, who actually can develop osteomyelitis spontaneously.
A chicken strain of Staphylococcus aureus that appears at the
endothelium within the capillaries of bones have gaps, and it
looks as if the organisms can actually access the capillary system
to these particular gaps. If you take a Staph aureus and
inject it into the blood of the chicken, within 12 hours you can see
bacteria in some of these capillaries, and subsequently a day or
two later, evidence of infection at the metaphyseal epiphyseal
junction. So this is sort of an interesting animal experiment,
perhaps showing that these epithelial gaps, at least in chickens,
play some role.
Another factor in the development of osteomyelitis, at least
relating to Staphylococcus aureus, is the organism that produces
this sort of slimy stuff seems to make it more adherent to various
portions of the bones and thus more commonly associated with
osteomyelitis than those other organs.
Microbial etiology of osteomyelitis. In the neonate, the organisms
most commonly associated with osteomyelitis are typically
Group B streptococcus and Staphylococcus aureus. Very small
babies may involve for various gram negative bacteria and certainly
cause osteomyelitis as well as some other bacteria. In the
infant and older child, Staphylococcus aureus is the most common
cause. Streptococcus is the second most common.
Highly encapsulated organisms are unusual causes of
osteomyelitis, but 3 to 5% of patients with acute osteomyelitis
will have pneumococcus as the etiology.
In the older child, the same types of organisms are seen. Salmonella
is an important pathogen in patients with sickle cell anemia.
With penetrating injuries, organisms associated with the soil or
the skin or on clothes can of course lead to infection. Some of
these injuries, such as injuries associated with lawn mower
trauma, can grind the soil-type organism into the skin and ultimately
into the bone.
Now, sacroiliitis is not necessarily specifically an osteo, it is an
osteo-like illness we must keep in mind, especially in dealing
with certain populations, especially those who are likely to ingest
under pasteurized or nonpasteurized dairy products.
IV drug abuse is associated with P. aeruginosa, hopefully not a
major problem in kids, but it certainly is something that is seen in
adults.
Chronic osteomyelitis is associated with gram negative organ

4
Clinical Manifestations of Osteomyelitis
..Fever, limitation of use of involved extremity or area.
. Localized swelling, warmth, erythema and pain (point tenderness)
. Pelvic osteomyelitis: hip and/or abdominal pain, difficulty walking, rectal
mass
. Vertebral osteomyelitis: back pain, tenderness over spinal processes
. Neonates-frequently accompanied by septic arthritis since epiphyseal,
metaphyseal junction within joint capsule; multiple bones Infected,
pseudoparalysis (high risk for sequelae
. Pseudomonas osteochondritis: foot puncture wound followed by local
findings in 48-96h; fever not prominent
isms. With fractures, this may lead to a chronic infection.
Contiguous infections which are not that common in pediatric
patients may be associated with anaerobic organisms. Perhaps
it is a decubitus ulcer, perhaps sinusitis, and after that may lead
to osteomyelitis of facial or scalp or skull bones.
Finally, certain fungi can disseminate and cause infection on the
bone.
The clinical manifestations of osteomyelitis include fever and
limitation of the extremity or the part of the body that is involved.
Localized swelling, warmth, erythema, and point tenderness
especially would be major clinical findings suggesting
osteomyelitis.
Now, outside of the extremities it could sometimes be very
difficult to pinpoint or even think about osteomyelitis. It could be a
subtle finding. For example, patients with pelvic osteomyelitis
may have a slight abdominal pain, perhaps they have some hip
pain or have some trouble walking, but when you examine their
extremities you really cannot pinpoint anything. It is not until you
do some more specific physical examinations, perhaps even a
rectal examination, that they sort of come up on this diagnosis.
Vertebral osteomyelitis typically occurs in older children with
back pain and tenderness when you palpate or stretch over the
spinal processes.
Finally, in neonates, one may see osteomyelitis in association
with septic arthritis because of the way the epiphyseal-
metaphyseal junction is actually positioned inside the joint, so
that the organism is able to rupture through the bone, it will
rupture into the joint space. In older children, typically if there is
a rupture through the periosteum; it will not rupture into the joint
space. Also, in contrast to what might happen in older children
where a single bone is what is most typically seen), in the neonate,
multiple bones are commonly infected.

5
Differential Diagnosis of Osteomyelitis and
Septic Arthritis
. Rheumatic fever
. Cellulitis
. Skeletal Neoplasia (Ewing's sarcoma, leukemia)
. Bone Infarction in hemoglobinopathy
. Hemophilia
. Thrombophlebitis
. Child Abuse/Trauma
. Toxic synovitis
. Appendicitis, UTI, Psoas abscess (Pelvic osteomyelitis)

6
Diagnosis of Osteomyelitis
. Laboratory
ESR or CRP elevated
Blood and bone aspirate cultures
. Radiology
Plain films - typical changes occur in 10-21 days (bone destruction,
periosteal new bone)
Tc99m Bone Scan - abnormal in over 90% (not as useful in neonates or
following fracture or surgery)
CT/MRI - may be helpful in unusual cases (pelvic, vertebral, skull)
Bone biopsy and culture - useful in unusual or chronic cases
Diagnosis of acute osteomyelitis. The erythrocyte sedimentation
rate is generally elevated. Other people like to get the C-reactive
protein and other nonspecific inflammatory laboratory tests. CRP
seems to come down more rapidly than the ESR. If there sed
rate is coming down slower, maybe I can draw out the therapy a
little bit longer.
From a radiographic standpoint, plain films are frequently helpful,
but generally they are useful later in the course because we
know they will not show specific changes for 7, 10 or 14 days.
This is how long it takes for decrease in bone mass to occur,
and that will show on your x-ray. Periosteal new bone formation
may also not be apparent for about 10 or 14 days.
The indications to undergo a technician bone scan. This is
abnormal in the vast majority of patients. It is not helpful in the
neonate, it is not helpful in those patients who have a fracture or
surgery. It is not helpful to patients with hemoglobinopathies
where an infarction and an infection cannot really be distinguished
by a typical bone scan.
In special situations, a CT and MRI could be particularly helpful.
This is especially true in patients that have pelvic osteomyelitis,
perhaps those with vertebral osteomyelitis. Then, many times
when it is not clear what is going on, you really would like to have
an organism, an actual bone biopsy as opposed to aspiration. A
biopsy where one can look at the bone under the microscope as
well as get a good culture can be very helpful.
I think these are most useful in the usual cases. The inflamed
bone is typically of osteomyelitis, for vertebral osteomyelitis they
are very helpful.
CT scans are very helpful. MRIs seems to be getting more
popular, and surgeons particularly like to obtain these types of
radiographic imaging prior to surgical approaches, so I think we
are going to see more MRI evaluations.

7
Antibiotic Management of Osteomyelitis
Organism Agent Duration (minimum)
S aureus Nafcillin/oxacillin
Alternatives:
clindamycin or
cefazolin
3 weeks and ESR <2030
mm/h
Neonate - 4 weeks
Streptococci penicillin as above
P aeruginosa
osteochondritis
Ticarcillin/Piperacillin +
aminoglycoside
7-10 days if adequate
debridement
Salmonella ampicillin if susceptible;
cefotaxime,
ceftriaxone,
TMP-SMX
3-4 weeks
Antibiotic management of acute osteomyelitis. I think that for the
straight forward cases, related especially to Staph aureus, a
typically nafcillin or oxacillin is initially provided and that can be a
good initial therapy. Antibiotics should be continued either IV or
orally for a minimum of three weeks, and shows that treatment
for less than three weeks in acute osteomyelitis will lead to more
relapses. So, greater than three weeks is what is recommended,
and typically four to six weeks is what is provided. I like to see
the sed rate below 30 mL per hour before I discontinue therapy. I
think that whether you should provide therapy intravenously or
orally is somewhat up to each individual and the parents, and
what their home situation is like, what can be done from the
home IV therapy standpoint, and whether the organism has been
isolated.

8
Management of Osteomyelitis
..Indications for Surgery
Drain purulent material from subperiosteal space or other tissue planes
Remove sequestra or infected foreign material
Débride and drain puncture associated infection
In neonate early drainage of bone and joint is critical
Chronic osteomyelitis
. Immobilize extremity
For Group A Streptococcus I think penicillin alone is fine.
Osteochondritis should be treated with a combination of antibiotics,
but an surgical debridement is most important.
For Salmonella, ampicillin is generally the treatment of choice if
the organism is susceptible to this antibiotic.
Serum titers, we are saying that we are taking a specimen of
blood at some point around the dose of an antibody before a
dose which would be the trough level or right after a dose IV,
perhaps an hour and a half after an oral dose would typically
represent the peak in the serum concentration and therefore test
the inhibition of the organism. You simply take the organism
which you hopefully have identified and have isolated in the
micro lab, and inoculate that into serial 2-fold solutions of this
serum.
As I mentioned, typically you like to treat these patients for four to
six weeks; either IV or orally depending on the organism and the
situations. Now, there are some times when you want to perform
surgical drainage; I think that if the surgeon went in to aspirate
the region or he might even see it on an MRI scan or CT scan,
there is an actual subperiosteal abscess that should be drained.
If there is a sequestra or there is swollen material within the
bones, that needs to be drained. In the neonate, these need to
be drained.

9
Etiology of Septic Arthritis and Age
Organism Neonate 2-36 months >36 months
S. aureus +++ +++ +++
S ,pneumoniae + + ++
S. pyogenes + +
Group B streptococcus +++
N. gonorrhoeae + + (adolescent)
Candida sp. ++
H Influenzae
(unimmunized) + ++ +
Salmonella (SSA) ++ ++
Kingella kingae ++
Puncture wounds of the foot frequently are caused by nail injuries
through the tennis shoe or some other shoe penetration and
inoculation of the bones. The majority of the patients have Pseudomonas
aeruginosa isolated either by itself or combination of
Staph aureus or streptococci.
When the surgeons explored the wounds, osteochondritis was
noted in all of the patients. There was also some septic arthritis
and some cutaneous abscesses also noted. So, the course of
exploration clearly is important. I think it is a conclusion that in
this infection, which is a infection of cartilage, that it is important
to perform the optimum surgery which would be to débride and
devitalize the infected soft tissue cartilage and bone. You need to
drain these joints. Then when you do that, one may only have to
treat with antibiotics for perhaps seven to ten days. So, this is in
contrast to what we are typically taught in treating osteomyelitis
for a prolonged period.
Organisms that cause septic arthritis in children. Again, in the
neonate, Staph aureus and Group B streptococcus are going to
be the leading organisms. Candida albicans and gram negative
are also apparent in premature infants. In the child between 2
and 36 months of age, Staph aureus is the most common. The
second most common is going to be pneumococcus. Salmonella
is something to think about in patients with
hemoglobinopathies. In older individuals Staph aureus, Group A
strep, and pneumococcus are the leading causes of septic
arthritis.

10
Clinical Manifestations of Septic Arthritis
..Acute onset fever, refusal to walk or limp
. Large joints (knee, hip, ankle) most common
. Swelling, warmth, erythema of joint with decreased mobility
. Abduction and external rotation is typical with hip
. In neonate systemic symptoms may be minimal
. In neonate multiple joints and contiguous osteomyelitis are common
. Small joints tend to be involved with gonococcal infection
Clinical manifestations of septic arthritis. We have the acute
onset of fever, refusal to walk, a limp would be the classic manifestation
in a baby. Perhaps the parents indicate that when they
change the diaper the baby is crying. Most of the time large joints
are involved. You might see a swelling, warmth, erythema, and
decreasing mobility in the joint. In the hip, the classic presentation
would be abduction and external rotation. In the neonate,
however, the symptoms may be very minimal. You might have
multiple joints involved and many bones infected as well, and it
is more or less hip. When you look at this baby you might see
that there is a slight dyssymmetry, and, in the baby, you may
illicit some pain on movement but it may be very subtle.

11
Differential Diagnosis of Septic Arthritis
..Nonbacterial infection- virus, hepatitis, Tb, fungi, Lyme disease
. Juvenile rheumatoid arthritis, other collagen vascular disease
. Acute rheumatic fever
. Inflammatory bowel disease
. Leukemia
. Toxic synovitis, psoas abscess, pelvic osteomyelitis (when unable to bear
weight)
. Reactive arthritis (Shigella, Yersinia, Salmonella; Endocarditis
. Trauma (hemarthrosis)
. Cellulitis

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Evaluation- Septic Arthritis
1. Blood cultures positive in approximately 40% of cases
2. Synovial fluid - culture and Gram-stain
WBC count/mm3 %PMN Fluid: blood
glucose
Septic arthritis >50,000 90% 999 (30%)
JRA <15-20,000 60% normal to 9
(75%)
3. Vaginal or urethral culture if appropriate
4. Plane Radiograph: soft tissue swelling, joint space widening, osteomyelitis
5. Bone joint Tc-99m Scan
In the evaluation of septic arthritis, a blood culture is very helpful
and in some studies it has been positive in up to 40% of patients.,
what you want to get is a sample of the synovial fluid, a
blood culture, and a gram stain. Classically, if the white blood
cell count of the synovial fluid is greater than 50,000 with predominance
of polys, then this most likely a bacterial infection. If
the count is between 15,000 to 20,000, maybe less than 10,000,
with a smaller proportion of polys and the glucose limit is normal,
this is more likely to be a juvenile rheumatoid arthritis or
some other collagen vascular disease.
If we are dealing with an adolescent, and GC is a consideration,
then vaginal or urethral cultures should be obtained. Sometimes
the plain radiography can give you some additional clues as to
the foreign body scenario and a bone joint scan can sometimes
be useful as well.

13
Empiric Antibiotics for Septic Arthritis
Age Agents Duration
Neonate Nafcillin/Vancomycin
+
aminoglycoside/
cefotaxime
3 weeks
Infant or child Nafcillin/oxacillin
add cefotaxime/
ceftriaxone
if no Hib vaccine
(cefuroxime)
3 weeks
S. aureus
2 weeks
H. Influenzae
Adolescent with presumed
GC
Ceftriaxone 7 days
Immunocompromised
child
Nafcillin/oxacillin plus
aminoglycoside
or
extended spectrum
cephalosporin
3 weeks
Empiric antibiotics for septic arthritis. Nafcillin is the drug that we
would use in the nursery now. Vancomycin might be started
initially because of what is going on in your nursery with the
aminoglycoside or cefotaxime. In the infant or child this should
read Nafcillin or oxacillin, plus cefotaxime regardless of Hib
immunization, because of the problem with penicillin is just a
pneumococcus. If one should have the organism then, I think you
can tailor the treatment more readily. In the adolescent,
ceftriaxone should be the drug.

14
Septic Arthritis: Indications for Surgery
..Join remains swollen and erythematous after repeat needle aspiration
. Removal of foreign material secondary to penetrating
. Hips should be drained surgically
. In neonate surgical drainage of most joints indicated
. Arthroscopic lavage of knee alternative to arthrotomy
Indications for surgery. If you have repeat aspiration of the joint
and it remains swollen and erythematous, surgery of the joint is
indicated to remove foreign material, certainly all hips should be
drained. Some people might say all shoulder infections as well.
In some situations you can actually do arthroscopy rather than
surgical incision and drainage. It depends on the site and size of
the joint. There are some risk factors for outcome for septic
arthritis that I have also provided for you.

15
Risk Factors for Sequelae of Septic Arthritis
..Young age <6-12 months (especially neonate)
. Prolonged duration of symptoms prior to treatment
. Hip and shoulder infection (especially with S. aureus
. Sequelae
Cartilage damage, stiff joint with poor mobility, abnormal bone growth if
epiphysis involved, unstable joint, chronic dislocation

16
Discitis - Clinical Manifestations
..Low-grade fever
. Infants: Refusal to sit, pain when changing diaper
. Young child: Hip or leg complaints, and refusal to walk or limps; irritable
. Older child with back pain, abdominal pain
. Pain on palpation over vertebral processes
. Paraspinal muscle spasm
. Differential diagnosis: Toxic synovitis, vertebral osteomyelitis, epidural
abscess, pelvic osteomyelitis, sacroiliitis (Brucellosis)
Discitis or disc space infection. This is more common in young
children. The history can be one of nominal pain, a back pain, or
difficulty walking, and a child not wanting to sit. The diagnosis is
typically made on plain film and bone scans. If you do an MRI or
CT on a patient, it can look terrible. Management is with an oral
antistaphylococcal agents and let the child ambulate as tolerated,
usually in their own room with bed rest.

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Discitis- Diagnostic Evaluation and Management
..Plan radiographs: disc space narrowing
. Bone scan: abnormal uptake in disc space and adjacent vertebral bodies
. MRI or CT are necessary if clinical and initial radiographic findings are not
typical
. Management: Rest and oral antistaphylococcal antibiotic for 34 weeks and
ESR <20 mm/hr

18
References
1. Gutman LT: Acute, subacute, and chronic osteomyelitis and pyogenic arthritis in
children. Curr Prob Pediatr 1985;15(12).
2. Jacobs RF, et al: Pseudomonas osteochondritis complicating puncture wounds of
the foot in children: a 10-year evaluation. J Infect Dis 1989;160:657-61.
3. Edwards MS, et al: Pelvic osteomyelitis in children. Pediatrics 1978;61:62-7.
4. Weinberg ED, et al: Clinical features of neonatal osteomyelitis. Pediatrics
1974;53:505-10.
5. Welkon CJ, et al: Pyogenic arthritis in infants and children: a review of 95 cases.
Pediatric Infect Dis 1986;5:669-76.
6. Cristin L, Sarosi GA: Pyomyositis in North America: case reports and review. Clin
Infect Dis 1992;15:668-77.
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Infect Dis J 1993;12:228.
8. Dangman BC, Hoffer JA, Rand FF, O'Rourke E J: Osteomyelitis in children:
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